Clauder et al. "IgG Fc N-glycosylation translates MHCII haplotype into autoimmune skin disease"

Published: 12-05-2020| Version 2 | DOI: 10.17632/9pgfdgjfc7.2
Contributors:
Ann-Katrin Clauder,
Anna Kordowski,
Yannic Bartsch,
Gabriele Köhl,
Gina-Maria Lilienthal,
Larissa N. Almeida,
Timo Lindemann,
Janina Petry,
Christina N. Rau,
Anna Gramalla-Schmitz,
Lara Dühring,
Claudia Elbracht,
Samyr Kenno,
Jenny Tillmann,
Manfred Wuhrer,
Ralf Ludwig,
Saleh M. Ibrahim,
Katja Bieber,
Jörg Köhl,
Marc Ehlers,
rudolf manz

Description

The major histocompatibility complex (MHC)-haplotype represents the most prevalent genetic risk factor for the development of autoimmune diseases. However, the mechanisms by which MHC-associated genetic susceptibility translates into autoimmune disease are not fully understood. Epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease driven by autoantibodies to type VII collagen (COL7). Here, we investigated autoantigen-specific plasma cells, CD4+ T cells and IgG Fc-glycosylation in murine EBA in congenic mouse strains with the disease-permitting H2s or -non-permitting H2b MHCII haplotypes. Mice with an H2s haplotype showed increased numbers of autoreactive CD4+ T cells and elevated IL-21- and IFN-γ-production, associated with a higher frequency of IgG autoantibodies with an agalactosylated, proinflammatory N-glycan moiety. Mechanistically, we show that the altered antibody glycosylation leads to increased ROS release from neutrophils, the main driver of autoimmune inflammation in this model. These results indicate that MHCII-associated susceptibility to autoimmune diseases acuminates in a proinflammatory IgG Fc N-glycosylation pattern and provide a mechanistic link to increased ROS release by neutrophils.

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